Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests: A model for reward pathology with effects of agomelatine

Abstract

A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity. continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity.

Modeling hypohedonia following repeated social defeat: Individual vulnerability and dopaminergic involvement

“…The present results are consistent with a recent study where defeated mice underperformed on PR tests for sucrose pellets following chronic social defeat (Bergamini et al 2016). However, the results differ from a report that social defeat led to persistent increases in operant performance for sucrose solution on a PR schedule (Riga et al 2015).…”

Selective amotivation deficits following chronic psychosocial stress in mice

“…The nucleus accumbens regulates motivation in mammals (Da Cunha et al, 2012), is essential for rearing (Lever et al, 2006), and CSD induces spine morphology alterations and increased synaptic transmission 20/38 amongst medium spiny inhibitory neurons in this area (Christoffel et al, 2011). In addition, we have demonstrated that CSD and dopamine depletion in the nucleus accumbens both lead to reduced motivation to obtain food reward under effortful conditions (Bergamini et al, 2016). These findings and others have made the nucleus accumbens a new potential target area to treat MDD through deep-brain stimulation (Nauczyciel et al, 2013), and raise the possibility that structural modifications within the nucleus accumbens, potentially instigated from hippocampo-amygdalar signalling, underlie the blunted drive to explore observed in this study.…”

“…There is therefore only a limited theoretical framework and narrow selection of tools currently available to probe the mechanisms underlying loss of exploratory drive in mental illness (Der-Avakian & Markou, 2012;Calabrese et al, 2014;Hershenberg et al, 2016). Given this minimal examination, and since better understanding exploration deficits could yield novel targets 6/38 and strategies for treating mental illness, we examined exploratory behaviours in mice following chronic social defeat (CSD), a social manipulation that induces pathophysiology reminiscent of MDD (Krishnan et al, 2007;Yan et al, 2010;Azzinnari et al, 2014;Fuertig et al, 2015;Grandjean et al, 2016;Bergamini et al, 2016).…”

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

“…CSS leads to reduced reward-directed behavior, 40,41 increased aversion learning, helplessness and fatigue, 38,42,43 increased fMRI restingstate functional connectivity within PFC and between PFC and amygdala, 44 increased amygdala inositol levels 44 and increased immune/inflammatory activation in periphery and amygdala and PFC. 38,41,42 Utilizing this depression-relevant model, the present study shows that CSS in mice leads to reduced expression of a number of oligodendrocyte genes in PFC and amygdala tissue comprising gray and white matter.…”